The effects of the endogenous antioxidant alpha-lipoic acid on guinea pig colon smooth muscle contraction (Gpcc) induced by hydrogen peroxide were examined. Having previously shown that the histone deacetylase (HDAC) benzamide inhibitor MGCD0103 inhibits guinea-pig smooth muscle contraction, as do various sulfur-containing antioxidants, we asked whether hybrid compounds possessing both alpha-lipoic acid-derived antioxidant properties and HDAC inhibitory activity could inhibit Gpcc.Guinea pig colon (Gpc) was incubated at 37A degrees C with Krebs buffer; the four stimulants-hydrogen peroxide, carbachol, histamine, and sodium fluoride-were added independently. The response to each stimulant alone was compared with that in the presence of each of the test compounds: MGCD0103, alpha-lipoic acid, and two of their hybrids, UCL M084 and UCL M109.NaF (10 mM), carbachol (0.05 mu M), histamine (0.1 mu M), and hydrogen peroxide (1 mu M) produced Gpcc of about 50-60% above basal level. With the exception of MGCD0103 against hydrogen peroxide, all four test compounds at 1 mu M-MGCD0103, alpha-lipoic acid, UCL M084, and UCL M109-produced a significant inhibition of 35-60% of Gpcc induced by hydrogen peroxide, NaF, and carbachol, although none reduced histamine or ovalbumin-induced Gpcc. Benzalkonium chloride (Bcl), a G-protein inhibitor, reduced the hydrogen peroxide-induced Gpcc by 35%.Contraction by stimulants used to induce Gpcc is known to involve G-proteins. All four test compounds-MGCD0103, alpha-lipoic acid and two of their hybrids, UCL M084 and UCL M109-reduced Gpcc induced by NaF and carbachol, suggesting that G-protein pathway involvement is relevant to the action of the test compounds, as is also indicated by the Bcl-induced inhibition of hydrogen peroxide-induced contractions. Additionally, alpha-lipoic acid and the two hybrids showed > 30% inhibition of hydrogen peroxide-induced contractions, consistent with the antioxidant properties of the 1,2-dithiolane ring.